Non-invasive imaging techniques are extensively used in development and characterization of small animal models of human disease as well as in discovery and evaluation of new therapeutics during pre-clinical studies. A large-scale volumetric imaging mode (whole body imaging) is extremely efficient for those tasks, since it allows simultaneous assessment of multiple regions and organs within the studied organism. Some well-established devices for in vivo imaging employ fluorescent methods and allow affordable, convenient, and highly sensitive interrogation of molecular microenvironments and physiological processes. However, at the same time, those devices suffer from poor spatial resolution, lack abilities to acquire high-fidelity volumetric images and reliable anatomical references. Additional high-resolution 3D imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MM) are frequently co-employed with fluorescence to assist in robust volumetric mapping of molecular specific information over anatomical structures of the animal. However, the instrumentation and imaging methods utilized in those add-on technologies operate on physical principles and require engineering solutions, which are completely different from the parent optical-type imaging, presenting significant technological and commercial barriers for multi-modal implementation. Attempts have been also made to improve the spatial fidelity of fluorescence images via tomographic reconstruction (fluorescence molecular tomography or FMT). However, low sensitivity, great complexity and slow image acquisition make those tomographic solutions impractical for the modern demands of high-throughput animal studies. Photoacoustic tomography (PAT) is an emerging hybrid biomedical imaging modality combining molecular contrast of optical imaging with high resolution of ultrasound. PAT of live mice was shown to provide high fidelity 3D anatomical maps of skin, vascular tree, and blood rich organs (kidney, spleen, liver, intestine, and heart) with less than 1 minute scans. However, due to strong background signals generated by native blood, its sensitivity to detection of fluorophores is inferior as compared to conventional fluorescence techniques. PAT is attractive from a perspective of its combination with fluorescence imaging, since it can use the same instrumentation for excitation of fluorescence and generation of photoacoustic effect. Combinations of FMT and PAT have been proposed with attempt to further improve accuracy of FMT images. However, those disclosed modalities still failed to sufficiently address problems of slow data acquisition, low sensitivity and inadequate anatomical registration.